Project Term
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Fred Hutchinson Cancer Center
Seattle, WA
United States
Project Summary
Genetic mutations in various RNA splicing factors occur in a significant percentage of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations can create abnormal proteins that contribute to disease development. Our research focuses on identifying these faulty proteins, specifically the small pieces (peptides) that are displayed on the surface of MDS and AML cells. We developed a novel method to uncover these faulty cell-surface peptides, and engineered specialized immune cells, called T cells, that recognize and kill leukemic cells carrying these faulty peptides. The goal of this proposal is to develop and translate into the clinic new T cell-based therapies to improve the outcomes of patients with high-risk leukemia.
Lay Abstract
Some of the most common genetic changes found in certain high-risk (HR) blood cancers—like myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML)—affect how cells process RNA, the instructions used to make proteins. Currently, there is a lack of curative therapies for many patients diagnosed with HR MDS and AML; therefore it is imperative to develop novel, paradigm-shifting therapeutic strategies. These changes, called splicing factor mutations, cause cells to create unusual versions of proteins not seen in healthy cells. The immune system can recognize small pieces of these abnormal proteins, called peptides, when they are displayed on the surface of cancer cells. This makes them excellent targets for new kinds of immunotherapy, which use T cells (a type of white blood cell) to find and destroy cancer. The goal of this proposal is to develop a comprehensive translational pipeline that integrates several key components: 1) the discovery of abnormal proteins present on the surface of leukemic cells using a novel technology platform called ARTEMIS, 2) genetic engineering of next-generation T-cells armored with enhanced ability to target and neutralize leukemic cells, and 3) clinical translation of engineered T-cells for the treatment of HR leukemia patients. Successful execution of this proposal will lead to safer, more personalized treatments—and potentially cures—for patients with hard-to-treat blood cancers.
Program